Identifying hidden target tissues using medical tools and guiding a medical instrument to target sites buried within the body are important medical skills. For example, detecting the presence or absence of prostate cancer with a medical probe would decrease the number of unnecessary biopsies. Similarly, using a medical instrument to detect the location of lymph nodes most likely affected by cancer prior to making a surgical incision would allow for a much smaller surgical incision and a less extensive surgical exploration. As another example, navigating a biopsy needle into a liver tumor would improve the chances that a physician will obtain an accurate biopsy specimen. Last, accurately knowing the margins of disease in a diseased organ would allow for the disease to be completely removed while sparing the maximum amount of normal tissue.
In order to achieve good detection and targeting of buried tissue, and to avoid a blind approach to a target site, many invasive procedures are attempted using medical instruments monitored or tracked using medical imaging or image guidance. A limitation of conventional imaging-based approaches is that they require an inherent, identifiable signal from the target tissue. An identifiable signal may be as simple as a different appearance on ultrasound or CT scan. However, key molecules in many disease processes may not possess strong, distinguishing features that allow them to be easily imaged. In such tissues, there may be no readily detectable difference from the surrounding tissue, and thus there will be little or no indication on a conventional image of the location of the target tissue or disease. Examples of this include the events associated with the activation of certain genes or cell surface receptors in the body, which may be important in the localization or detection of certain cancers. Prostate cancer, for example, is not well seen on CT, MRI, or ultrasound. As a result, even when prostate cancer is present at the time of biopsy, 20% of all prostate biopsies will be falsely negative for cancer. Other examples include the events associated with infection, which may be important in the selection of an appropriate antibiotic therapy. Thus, conventional imaging is limited in that it fails for many types of diagnostic and therapeutic procedures that would in theory benefit from image guidance.
Contrast agents have been used in the past for medical monitoring and imaging when the inherent or native signal in vivo is absent or poor. A contrast agent serves to provide a strong, identifiable signal to an otherwise poorly detectable tissue site. In this regard, use of contrast is known in the art, and is a routine part of conventional imaging approaches such as CT, MRI, and occasionally ultrasound.
A drawback to ultrasound contrast is that the contrast has tended to consist of physical agents, such as bubbles, which are limited in that they have not been tissue targetable and have been short lived. This makes such agents poor for real time localization and targeting. Many types of site-specific binding moieties are known, including antibodies (e.g., U.S. Pat. No. 5,851,527) and nuclear receptors (e.g., U.S. Pat. No. 5,840,507), and these can be used for targeted delivery of contrast agents. Targetable contrast has been reported for use in vitro and in vivo for MRI and nuclear medicine (e.g., U.S. Pat. No. 5,861,248). However, use of targeted MRI, nuclear medicine, and CT contrast agents is limited by their low contrast. A targeted MRI contrast agent, for example, may increase the native signal by only 20-50% over MRI background. This reduces the ability to detect small lesions, and makes real time targeting more difficult.
Another disadvantage to the use of contrast agents in CT and MRI is that most CT and MRI systems do not operate in real time (real-time MRI exists, but is awkward to use and expensive). However, patients are not static objects. Tissues move and organs shift, so that a CT or MRI image obtained even a few minutes before a procedure may no longer be accurate when needed as an image guidance reference. For example, the liver moves with breathing, and the prostate and breast move with changes in position. Thus, the location of a tumor on the CT or MRI scan with respect to a marker on the patient can change. Similarly, many CT and MRI image guided systems use images collected prior to an intervention, and do not reflect any interaction of a tool with the body. Thus, when the brain moves during neurosurgery, an image that was correct before the skull was opened may now be dangerously inaccurate. Therefore, in the absence of real-time feedback, many image guided surgery techniques that rely on static images can prove inaccurate.
Use of contrast that is optically based raises the possibility of real-time, portable guidance and monitoring. In this regard, contrast agents that have optical properties detectable in vivo are known. For example, cardiac output, liver function, lung blood flow, brain blood flow, and retinal blood flow/transparent structure have been measured or in vivo or ex vivo using optical dyes (e.g., U.S. Pat. No. 5,494,031, Patel et al. in Ped Res 1998;43(1):34-39). In these examples, the contrast agent is used to measure a bodily function, such as blood flow or enzymatic clearance from the bloodstream. The concentration of a drug or dye has also been measured in the bloodstream (e.g., U.S. Pat. No. 4,805,623). However, none of the preceding optical contrast methods or devices teach detection or localization of contrast distribution through opaque tissue, nor detection or localization of tissue types. Further, these systems are not coupled to medical devices or instruments used in the performance of a medical procedure, nor do they allow targeting of invasive medical instrument to specific tissue sites.
More recently, new optical dyes have been reported that may have application to real-time optical localization and targeting (e.g., U.S. Pat. No. 5,672,333, U.S. Pat. No. 5,698,397, WO 97/36619, WO 98/48838, Huber et al. in Bioconjugate Chem 1998;9:242-249). These dyes are useful for microscopy or in vitro or in vivo, and some have multimodality functionality for both MRI and optical imaging. The listed patents add to the list of optical agents available for use in the body, but do not demonstrate or suggest systems for their use in medical devices or instruments for the detection or localization of target tissues, nor do they suggest or teach methods for the targeting of invasive medical instruments to specific tissue sites.
Optical methods have been developed for both external imaging and for incorporation into medical devices. Devices for imaging or measuring spectroscopic features of living tissue include U.S. Pat. No. 5,137,355, U.S. Pat. No. 5,203,339, U.S. Pat. No. 5,697,373, U.S. Pat. No. 5,722,407, U.S. Pat. No. 5,782,770, U.S. Pat. No. 5,865,754, WO 98/10698, Hintz et al. in Photochem Photobiol 1998;68(3):361-369, and Svanberg et al in Acta Radiologica 1998;39:2-9. One drawback to these systems is that they are typically large, bulky imaging systems, and some are quite expensive. Another drawback is that many of these devices are not configured for incorporation into medical tools or instruments. In fact, many teach away from coupling to a medical device or instrument, relying instead on a noncontact or noninvasive imaging system. Some of these are non-penetrating systems, such as endoscopes, or non-contact systems. Such systems are superficial imaging systems that merely image the surface of a tissue, and they do not image through opaque tissues to allow detection and targeting of deep tissues, nor is it obvious how such endoscopic or external imaging systems would readily be coupled into medical or surgical tools to penetrate through tissue to reach deep tissue sites. Another disadvantage is that many of these systems teach away from use of contrast, relying instead upon native spectroscopic signals. For those approaches that do suggest concurrent use of optical contrast agents, such as indocyanine green, coupling of these systems to medical instruments using exogenous contrast to locate or target specific tissue sites hidden through opaque tissue is neither taught nor suggested, nor is use of a contrast agent for the targeted delivery of an invasive device to a target tissue suggested or taught. In fact, these devices teach away from use in invasive tools, featuring noninvasive or endoscopic use as a strength, and none of these systems is well suited for use as an invasive device.
Invasive or contact-marking medical instruments equipped with optics, such as catheters, needles, and trocars, include U.S. Pat. No. 5,280,788, U.S. Pat. No. 5,303,026, U.S. Pat. No. 5,349,954, U.S. Pat. No. 5,413,108, U.S. Pat. No. 5,596,992, U.S. Pat. No 5,601,087, U.S. Pat. No. 5,647,368, U.S. Pat. No. 5,800,350, and others. Some of these devices are endoscopic, and do not image through opaque tissue. Others are invasive medical instruments and devices, but they do not detect or localize target tissues using exogenous contrast, nor do they allow targeting of an instrument to specific tissue sites using an in vivo contrast signal from an exogenous contrast agent. Several of these patents explicitly teach away from the use of contrast.
An alternative to the use of a contrast agent is use of an emitting reporter. In this regard, use of emitting reporters is known in the art. For example, in nuclear medicine and PET scanning, agents that spontaneously emit a particle or photon provide a signal to identify to localization of the emitter agent. Targeted instruments based upon non-optical emitters have been built (e.g., U.S. Pat. No. 5,857,463). A drawback to nearly all emitter-based systems is that they suffer from low signal, which is due to use of radioactive or ionizing emitters that produce a signal only intermittently (such as a particle decay) and at low intensity, forcing long integration times that make real time imaging and precise localization slow or difficult. This low signal presents a particular difficulty when using a moving medical instrument, or when targeting a tissue using a moving probe, both of which require a strong signal for reliable, rapidly updated real time analysis.
An optical equivalent to the external imaging of emitter reporters is use of light-emitting beacons that spontaneously generate light, such as the luciferase protein family. Such approaches are not contrast agents in the sense of this invention, as optical contrast agents modify the incident radiation rather than spontaneously generate light as is done using emitting optical reporters. An additional drawback for optical emitting reporters, beyond those shared by all emitting reports, is that they require a nearly light-free environment, making use real-time in vivo in humans difficult. Of note, such optical emitting reporters have not been coupled to a medical devices, such as an invasive targeted therapeutic device.
None of the above systems, agents, or methods suggest how to combine an optical contrast agent and a medical tool or instrument into a coherent system for tissue localization and targeting, nor how to perform optical contrast-guided surgery, nor how to target invasive instruments toward tissue using the tracking signal of an optical contrast agent, nor how to identify target tissues using a medical tool based upon the localization and distribution of an optical contrast agent. A real-time optical system and method to guide devices to target tissue sites, or to detect, localize, and image tissue targets using a contrast-influenced signal passing through opaque tissue to a medical tool, has not been taught, nor has such a tool been successfully commercialized.